Lead has been shown to inhibit protein synthesis by rabbit reticulocytes at concentrations as low as 1.0 mu M. Although a great deal has been learned about the steps involved in protein synthesis the precise point in this process which is so sensitive to lead has not yet been determined. The objective of this proposal is therefore to uncover the mechanism of the inhibition of protein synthesis by lead. Soluble lead salts can catalyze the depolymerization of RNA in vitro. There is little knowledge, however, as to the effects of lead on RNA in vivo. In order to determine the effects of lead on the different types of RNA in vivo the integrity of polyribosomes, the molecular weight of RNA and the ability of transfer RNA to participate in protein synthesis will be compared for RNA obtained from normal cells and for cells exposed to low levels of lead. Lead may also cause depolymerization of RNA in vivo by another mechanism. Many mammalian cells contain latent nuclease activity. Lead, mercury and other heavy metals can activate these latent nucleases bringing about enzymatic degradation of cellular nucleic acids. A genetic lesion leading to activation of the latent nuclease in mice brings about a condition resembling human muscular dystrophy. One of the purposes of this grant is to study the activation of latent nucleases by lead and other heavy metals. These studies might explain the neuromuscular symptoms in lead and other heavy metal poisoning. Lead has also been implicated as the cause of chromosome breaks and the mechanism is not known. Lead is a component of most gasolines and an atmospheric contaminant. It was also an ingredient in house paint and lead poisoning has become a serious health problem due to the prevalance of pica (plaster eating) among the children of urban ghettos. Mercury has been shown to cause destruction of cellular RNA via the latent nuclease activation mechanism. It is also a water contaminant. Therefore, this study could give some indication as to the degree to which cellular RNA is degraded and protein synthesis is impaired by lead and other heavy metal contaminants.